Structural Implications for Selective Targeting of PARPs

Steffen, Jamin D.; Brody, Jonathan R.; Armen, Roger S.; Pascal, John M.

doi:10.3389/fonc.2013.00301

Cited by 131 publications

(154 citation statements)

References 92 publications

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“…1). Although other structural aspects of the PARP superfamily proteins, including inhibitor selectivity, have been extensively studied and thoroughly reviewed elsewhere (Ferraris, 2010;Ekblad et al, 2013;Papeo et al, 2013;Steffen et al, 2013), the scope of this review will be limited to the structural data on PARP1, the most-studied DNA-dependent enzyme of the PARP superfamily, focusing on those inhibitors for which PARP-trapping activity has been evaluated or their closely related analogs for which cocrystal structures are publicly available for analyses ( Fig. 1).…”

Section: Current View Of Parp-trapping Structureactivity Relationshipmentioning

confidence: 99%

“…2A) has been exploited extensively in the development of PARP inhibitors, including those in late-stage clinical development ( Fig. 1) (Ferraris, 2010;Ekblad et al, 2013;Papeo et al, 2013;Steffen et al, 2013). Within the relatively large NAD 1 -binding site, these inhibitors exhibit a range of diverse binding modes targeting distinct binding regions (Fig.…”

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 99%

“…The core carboxamide moiety, shared among these PARP inhibitors, forms critical hydrogen bonds with conserved Gly863 and Ser904 residues ( Fig. 2B) (Ferraris, 2010;Ekblad et al, 2013;Papeo et al, 2013;Steffen et al, 2013). These inhibitors also contain an aryl (and sometimes a bicyclic) ring system forming p-stacking interactions with conserved Tyr896 and Tyr907 residues (Fig.…”

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 99%

“…Other conserved residues bordering the nicotinamide pocket, such as pocket-forming Ala898 and Lys903, and a predicted catalytic residue (Glu988) (Ruf et al, 1998) have also been exploited in the design of inhibitors ( Fig. 2B) (Ferraris, 2010;Ekblad et al, 2013;Papeo et al, 2013;Steffen et al, 2013). Veliparib, the smallest PARP inhibitor in clinical development, binds within the NAD 1 -binding site primarily through critical interactions with or near the nicotinamide-binding residues.…”

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 99%

“…2A). Many known PARP1 inhibitors leverage the presence of this adenine-ribose subsite by incorporating a large hydrophobic group onto the core nicotinamide pharmacophore (Ferraris, 2010;Ekblad et al, 2013;Papeo et al, 2013;Steffen et al, 2013). An early preclinical PARP1 inhibitor, FR257517 (IC 50 , 14 nM) (Fig.…”

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 99%

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Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

191

188

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Recent findings indicate that a major mechanism by which poly (ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for singleagent and combination treatments.

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Section: Current View Of Parp-trapping Structureactivity Relationshipmentioning

confidence: 99%

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 99%

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 99%

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 99%

Section: Inhibitor Binding In Parp1 Cat Domainmentioning

confidence: 99%

See 3 more Smart Citations

Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

191

188

View full text Add to dashboard Cite

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The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

Rimar

Tran

Matulewicz

et al. 2017

Cancer

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As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single or double- strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or following a latency period cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. While the application of PARP inhibitors (PARPis) was initially focused on tumors with BRCA1 or BRCA2 deficiency, our current knowledge has extended synthetic susceptibilities of PARPi to deficiencies in proteins and pathways involved in DNA damage repair (DDR) in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder, and especially prostate cancers, contain subsets of patients with germline and somatic alterations in HR genes that may reflect increased response to PARPis. In this review, we describe the mechanisms and rationale of PARPi use in GU cancers, summarize previously reported pre-clinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can be applied for widespread application in GU cancers.

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Triumphs and challenges in exploiting poly(ADP‐ribose) polymerase inhibition to combat triple‐negative breast cancer

Wooten

Mavingire

Damar

et al. 2023

Journal Cellular Physiology

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Poly(ADP‐ribose) polymerase 1 (PARP1) regulates a myriad of DNA repair mechanisms to preserve genomic integrity following DNA damage. PARP inhibitors (PARPi) confer synthetic lethality in malignancies with a deficiency in the homologous recombination (HR) pathway. Patients with triple‐negative breast cancer (TNBC) fail to respond to most targeted therapies because their tumors lack expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Certain patients with TNBC harbor mutations in HR mediators such as breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), enabling them to respond to PARPi. PARPi exploits the synthetic lethality of BRCA‐mutant cells. However, de novo and acquired PARPi resistance frequently ensue. In this review, we discuss the roles of PARP in mediating DNA repair processes in breast epithelial cells, mechanisms of PARPi resistance in TNBC, and recent advances in the development of agents designed to overcome PARPi resistance in TNBC.

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Structural Implications for Selective Targeting of PARPs

Cited by 131 publications

References 92 publications

Trapping Poly(ADP-Ribose) Polymerase

Trapping Poly(ADP-Ribose) Polymerase

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

Triumphs and challenges in exploiting poly(ADP‐ribose) polymerase inhibition to combat triple‐negative breast cancer

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